In Orientals, ALDH2 deficiency due to the common polymorphism Glu487Lys frequently causes a flushing reaction after alcohol consumption and this aversive reaction is responsible for lower rates of alcoholism in individuals with the inactive Lys487 allele. R. Peterson identified a series of additional markers at ALDH2. By restriction enzyme analysis, SSCP, and sequencing, haplotypes characteristic for the two ALDH2 alleles were identified. This analysis has shed light on the origins and functional role of the Lys487 allele, which appears to have originated once, on a single haplotype lineage, and spread among East Asian populations. Furthermore, although it probably originated on a single genetic background, haplotype analysis reveals that the mutation was sufficiently ancient for additional mutations to have occurred subsequently. The results on ALDH2 haplotypes are most compatible with an effect of selection to maintain the Oriental ALDH2 variant, Glu487Lys. We have studied ADH haplotype structure with our collaborators at Yale University. These studies have yielded a new ADH1C amino acid substitution, an appreciation of the haplotype structure of the ADH gene complex on chromosome 4, and some evidence for reduction in haplotype diversity, potentially attributable to a selective sweep in this chromosome region.We are investigating the relationship of ADH and ALDH functional alleles to alcoholism and other substance abuse phenotypes. These genotype/phenotype relationships are being studied in combination with other loci, for example the OPRM1 receptor locus in opioid addiction. We genotyped two SNPs of the ADH and ALDH2 genes and analyzed the association with heroin abuse in a large Chinese sample and using highly efficient, accurate 5'exonuclease assays we developed for the polymorphisms. The results have shown no association between ADH, ALDH, and Chinese opioid addicted subjects. There is also no association between OPRM, 118A to G, OPRD, 307T to C SNPs and opioid addicts. Recently, we developed a large SNP array for haplotype analysis of the chr 4 ADH cluster region, a region which has in our SW Indian study and the COGA study shown linkage to alcoholism.